高尿酸通过活化泛素羧基末端水解酶Uchl1进而诱导血管内皮功能障碍的机制研究

高尿酸与心血管疾病的相关性备受关注。我们临床研究提示高尿酸血症与动脉狭窄密切相关，细胞实验提示高尿酸上调脐静脉内皮细胞(HUVECs)的肾素（前体）受体[(P)RR]进而激活肾素血管紧张素系统(RAS)及炎症通路，导致血管内皮功能障碍，但分子机制不清。本课题用尿酸酶敲除(UOX KO)构建高尿酸小鼠模型。UOX KO小鼠出现内皮依赖性血管舒张功能障碍及血压升高，血管(P)RR蛋白水平显著增高伴RAS激活，血管蛋白质组学提示去泛素化酶Uchl1显著升高。有研究提示(P)RR蛋白可被泛素化降解。因此，本研究拟在UOX KO小鼠和高尿酸刺激的HUVECs中，分别利用血管内皮特异性Uchl1基因敲除或Uchl1抑制剂干扰，阐明高尿酸通过活化Uchl1进而减少(P)RR的泛素化降解，上调(P)RR蛋白水平，激活RAS及下游炎症，导致血管内皮功能障碍，为防治高尿酸血症致血管功能障碍提供新的药物靶点。

Hyperuricemia is closely related to inflammatory cardiovascular diseases. Our previous clinical research has suggested that hyperuricemia is significantly associated with arterial stenosis. Our cell research have shown that higher uric acid (HUA) activates inflammatory pathways such as (pro)renin receptor [(P)RR)] and renin angiotensin system (RAS) in umbilical vein endothelial cells (HUVECs), leading to vascular endothelial dysfunction. However, the molecular mechanism is still unclear. Therefore, we introduced uricase knockout (UOX KO) mice to establish a hyperuricemia mice model. Our study showed increased expression of (P)RR and RAS activation, evoked endothelial dependent vasodilation dysfunction and elevated blood pressure in UOX KO mice. Additionally, proteomics showed that ubiquitin carboxyl terminal hydrolase Uchl1 also increased significantly. (P)RR was reported to be degraded by ubiquitin-proteasome. It is supposed that HUA up-regulated Uchl1 increases the (P)RR expression via deubiquitination, then activates downstream RAS and inflammation pathway, leading to vascular endothelial dysfunction. Therefore, we will apply vascular endothelium-specific Uchl1 gene knockout or Uchl1 inhibitor in UOX KO mice and HUA-treated HUVECs, respectively. Finally, we aim to provide a new drug target for clinical prevention and treatment of hyperuricemia-induced vascular dysfunction.